Eccrine Squamous Syringometaplasia Associated With Lichen Sclerosus et Atrophicus.

ABSTRACT: Eccrine squamous syringometaplasia (ESS) has been associated with several conditions including morphea, linear scleroderma, and burns. It is yet to be reported in lichen sclerosus et atrophicus (LSA). We describe a bullous LSA plaque on the forearm of a woman with pre-existing genital LSA and vitiligo. Besides the histopathological findings of bullous LSA, numerous small irregular squamoid structures were present in the mid and upper dermis always above the normal eccrine glands. The histopathology, periodic acid-Schiff stain, and positive immunostains for P63, low molecular weight keratins 8&18, epithelial membrane antigen, and carcinoembryonic antigen supported the diagnosis of ESS. The pathogenesis of ESS in LSA may be related to ischemia, inflammation, and fibrosis.

Global CpG DNA Methylation Footprint in Kaposi's Sarcoma.

Kaposi's sarcoma-associated herpesvirus (KSHV), also familiar as human herpesvirus 8 (HHV-8), is one of the well-known human cancer-causing viruses. KSHV was originally discovered by its association with Kaposi's sarcoma (KS), a common AIDS-related neoplasia. Additionally, KSHV is associated with two B-lymphocyte disorders; primary effusion lymphoma (PEL) and Multicentric Castlemans Disease (MCD). DNA methylation is an epigenetic modification that is essential for a properly functioning human genome through its roles in chromatin structure maintenance, chromosome stability and transcription regulation. Genomic studies show that expressed promoters tend to be un-methylated whereas methylated promoters tend to be inactive. We have previously revealed the global methylation footprint in PEL cells and found that many cellular gene promoters become differentially methylated and hence differentially expressed in KSHV chronically infected PEL cell lines. Here we present the cellular CpG DNA methylation footprint in KS, the most common malignancy associated with KSHV. We performed MethylationEPIC BeadChip to compare the global methylation status in normal skin compared to KS biopsies, and revealed dramatic global methylation alterations occurring in KS. Many of these changes were attributed to hyper-methylation of promoters and enhancers that regulate genes associated with abnormal skin morphology, a well-known hallmark of KS development. We observed six-fold increase in hypo-methylated CpGs between early stage of KS (plaque) and the more progressed stage (nodule). These observations suggest that hyper-methylation takes place early in KS while hypo-methylation is a later process that is more significant in nodule. Our findings add another layer to the understanding of the relationship between epigenetic changes caused by KSHV infection and tumorigenesis.

Molecular epidemiology of non-syndromic autosomal recessive congenital ichthyosis in a Middle-Eastern population.

Autosomal recessive congenital ichthyosis (ARCI) is a rare and heterogeneous skin cornification disorder presenting with generalized scaling and varying degrees of erythema. Clinical manifestations range from lamellar ichthyosis (LI), congenital ichthyosiform erythroderma (CIE) through the most severe form of ARCI, Harlequin ichthyosis (HI). We used homozygosity mapping, whole-exome and direct sequencing to delineate the relative distribution of pathogenic variants as well as identify genotype-phenotype correlations in a cohort of 62 Middle Eastern families with ARCI of various ethnic backgrounds. Pathogenic variants were identified in most ARCI-associated genes including TGM1 (21%), CYP4F22 (18%), ALOX12B (14%), ABCA12 (10%), ALOXE3 (6%), NIPAL4 (5%), PNPLA1 (3%), LIPN (2%) and SDR9C7 (2%). In 19% of cases, no mutation was identified. Our cohort revealed a higher prevalence of CYP4F22 and ABCA12 pathogenic variants and a lower prevalence of TGM1 and NIPAL4 variants, as compared to data obtained in other regions of the world. Most variants (89%) in ALOX12B were associated with CIE and were the most common cause of ARCI among patients of Muslim origin (26%). Palmoplantar keratoderma associated with fissures was exclusively a result of pathogenic variants in TGM1. To our knowledge, this is the largest cohort study of ARCI in the Middle-Eastern population reported to date. Our data demonstrate the importance of population-tailored mutation screening strategies and shed light upon specific genotype-phenotype correlations.

Histopathological Findings in Nail Clippings With Periodic Acid-Schiff-Positive Fungi.

BACKGROUND: Periodic acid-Schiff (PAS) staining of nail clippings is an adjunct diagnostic tool for onychomycosis. OBJECTIVE: To detect histopathological findings as clues to the presence of PAS-positive (+) fungal elements in nail clippings. METHODS: Four hundred sixteen consecutive nail clippings suspected of onychomycosis were stained with hematoxylin and eosin, and with PAS stains. All cases were studied histopathologically. The clinical files of the cases with neutrophils were reviewed. RESULTS: PAS+ staining for fungi were demonstrated in 159 (38%) of the nail clippings. Neutrophils, parakeratosis, plasma globules, and bacteria were observed in 43 (27%), 108 (67%), 80 (50%), and 80 (50%) of the PAS+ cases, respectively, and in 17 (6%), 109 (41%), 84 (32%) and 140 (54%) of the PAS- cases, respectively (P < 0.01). Neutrophils showed by far the highest specificity (93%), although with low sensitivity (27%) for the presence of PAS+ fungi. Among the 43 PAS+ and 17 PAS- specimens with neutrophils, only 1 (2.3%) and 3 (17%) had overt psoriasis, respectively. CONCLUSION: Neutrophils in nail clippings may serve as a clue for onychomycosis. PAS staining with neutrophils is not necessarily associated with psoriasis.

Neonatal Autoimmune Subepidermal IgG/IgA Blistering Disease With Severe Laryngeal and Esophageal Involvement: A Report of a Case and Review of the Literature.

Neonatal autoimmune subepidermal blistering disease is rare. Mucosal involvement is more common in neonatal linear immunoglobulin A (IgA) bullous dermatosis. We describe a neonate with subepidermal cutaneous blistering disease with severe laryngeal and esophageal involvement leading to acute respiratory distress. Histopathology demonstrated a subepidermal blister with neutrophils and eosinophils at the dermal base. Collagen IV was detected at the dermal floor, and direct immunofluorescence showed linear IgG, IgA, and C3 deposits at the basement membrane zone. The patient demonstrated markedly increased serum levels of anti-BP180 NC16A and anti-BP230 IgG antibodies (Abs) but failed to show anti-LAD-1 IgA Abs. His healthy mother showed serum anti-LAD-1 IgA Abs but did not show anti-BP180 and anti-BP230 Abs. The neonate responded promptly to systemic corticosteroid therapy. A review of the literature detected 11 cases of neonatal subepidermal blistering disease with linear IgA deposits. Nine of these cases demonstrated coexisting linear IgG deposits, often with C3. Respiratory compromise was present in most of the cases. Neutrophils and eosinophils were commonly present in the inflammatory cell infiltrates. Besides our case, 2 cases of neonatal IgG/IgA subepidermal blistering disease with esophageal involvement were previously described. IgA Abs were present in the sera of both cases. Anti-LAD-1 IgA Abs were detected in the mother's serum of our case alone, but IgA Abs do not cross the placenta. Our case was consistent with neonatal IgG/IgA pemphigoid. Neonatal IgG/IgA subepidermal blistering disease may be associated with severe laryngeal and esophageal involvement leading to respiratory compromise. Expedited diagnosis and prompt treatment are warranted.

Oral propranolol administration is effective for infantile hemangioma in late infancy: A retrospective cohort study.

The highest efficacy of oral propranolol is for infantile hemangioma (IH) in the proliferative phase. Evaluation of the effectiveness of oral propranolol is less established when it is administered in late infancy following the proliferative phase. We aimed to assess the clinical outcomes of pediatric patients managed by oral propranolol beyond the proliferative phase of IH. A retrospective cohort study in a tertiary health care referral center was conducted to track all patients with IH receiving systemic propranolol following the proliferative phase. Twenty-eight eligible patients were managed by 2 to 3 mg/kg per day of oral propranolol for IH beyond the proliferative phase, defined at 9 months of age. The mean age at the initiation of propranolol was estimated at 11.25 (SD 2.24) months. All eligible patients experienced some degree of clinical resolution, with the average improvement rate being estimated at 77.1% (SD 16.1). Comparable results were achieved among patients who were placed on propranolol at an age older than 12 months and those managed between the age of 9 and 12 months. No serious adverse events were observed during the follow-up duration. In conclusion, oral propranolol is a safe and effective treatment for patients with IH initiating this agent beyond the proliferative phase.

[AT THE BOTTOM OF THE ULCER - THE IMPORTANCE OF A BIOPSY IN DIAGNOSING HARD TO TREAT ULCERS].

INTRODUCTION: We report a case of a patient who presented with bilateral chronic painful necrotic leg ulcers. A skin biopsy revealed histopathological findings compatible with calciphylaxis, a rare phenomenon accompanied by high morbidity and mortality. Treatment options are limited and are based mainly on case reports and small series, so further research is needed in this area. This case highlights the importance of a skin biopsy in the diagnosis of chronic ulcers.

Primary Cutaneous Clonal CD8+ T-Cell Lymphoproliferative Disorder Associated With Immunodeficiency due to RAG1 Mutation.

The development of T-cell lymphomas, granulomatous reactions, and autoimmunity has been observed in immunodeficiency due to milder forms of recombination activating gene (RAG) deficiency. A few cases of cutaneous clonal papulonodular CD8 lymphocytic infiltrates and cutaneous CD8 granulomatous T-cell lymphoma have been described in association with common variable immunodeficiency, and with X-linked agammaglobulinemia. We describe a 15-year-old girl with several autoimmune disorders and recurrent infections that presented with several nodules on her cheek. Histopathological studies demonstrate histological, immunohistochemical, and molecular findings compatible with a primary cutaneous clonal CD8 T-cell lymphoproliferative disorder. Vacuolar interface changes were also seen in the involved skin, reminiscent of cutaneous lupus erythematosus. Molecular genetic analysis revealed a germline novel homozygous missense mutation in RAG1 (T1003>C). The parents were heterozygous carriers. The facial cutaneous lesions recurred despite local radiation therapy. Because of recurrent life-threatening systemic infections, allogeneic bone marrow transplantation was performed. The pathogenesis of this primary cutaneous clonal CD8 T-cell lymphoproliferative disorder may have been related to a chronic stimulation of autoreactive T cells in the involved skin paired with reduced RAG1 activity.

Follicular eruption with folliculotropic lymphocytic infiltrates associated with anti-tumor necrosis factor alpha therapy: Report and study of 3 cases.

BACKGROUND: We have encountered three cases of follicular eruptions with folliculotropic infiltrates of non-atypical lymphocytes associated with anti-tumor necrosis factor alpha (TNF-α) therapy. METHODS: Three patients aged 15 to 56 years treated with anti-TNF-α therapy (one with adalimumab, and two with infliximab) developed follicular eruptions characterized histopathologically by folliculotropic lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly. RESULTS: All three cases were characterized histopathologically by folliculotropic cell infiltrates of non-atypical T (CD3+) lymphocytes with variable follicular exocytosis. Marked reduction in CD7 staining and marked predominance of CD4+ cells over CD8+ cells were observed in 1 and 2 cases, respectively. T-cell receptor (TCR) gene rearrangement studies were monoclonal in 1 case. Discontinuation of anti-TNF-α therapy in all three cases, with corticosteroid creams in 1 case, led to complete resolution. Rechallenge with adalimumab in 1 case resulted in exacerbation. Replacement of therapy with non-anti-TNF-α biologic agents in 2 cases was not associated with recurrence. CONCLUSION: Follicular eruptions with folliculotropic lymphocytic infiltrates associated with anti-TNF-α therapy may show some immunophenotypical variations and/or monoclonal TCR gene rearrangements but lack sufficient cytomorphological features of folliculotropic MF. They may resolve with discontinuation of anti-TNF-α therapy.

Follicular Eruption With Folliculotropic Lymphocytic Infiltrates Associated With Iatrogenic Immunosuppression: Report and Study of 3 Cases, and Review of the Literature.

BACKGROUND: Several cases of folliculotropic mycosis fungoides, associated with immunosuppressive therapy, including calcineurin inhibitors, have been reported in solid organ transplant patients. We have encountered 3 patients on immunosuppressive therapy who developed follicular eruptions with folliculocentric infiltrates of nonatypical lymphocytes. OBJECTIVE: To characterize these follicular eruptions and review the literature. METHODS: Three patients, aged 7-15 years, who were treated with systemic immunosuppressive therapy developed follicular eruptions characterized histopathologically by folliculocentric lymphocytic infiltrates. These were studied clinically, histopathologically, immunophenotypically, and molecularly for T-cell receptor (TCR) gene rearrangement. RESULTS: All 3 cases were characterized histopathologically by folliculocentric infiltrates of nonatypical CD3 T lymphocytes with variable follicular exocytosis. Two cases also showed follicular mucinosis. Marked reduction in CD7 staining, and marked predominance of CD4 cells over CD8 cells was observed in all 3 cases. The TCR gene rearrangement studies were monoclonal in 2 cases. Oral calcineurin inhibitors (2 cyclosporine A and 1 tacrolimus) were part of the therapeutic regimen in all 3 patients. Their cessation along with local corticosteroid creams in 2 patients, and phototherapy with oral acitretin in one patient, was associated with complete clinical remission. CONCLUSIONS: Patients undergoing systemic immunosuppressive therapy that includes calcineurin inhibitors might develop follicular eruption with some immunophenotypical variations and a monoclonal TCR gene rearrangement but lack sufficient cytomorphological features of folliculotropic mycosis fungoides. Altering the immunosuppressive agent including calcineurin inhibitors may result in regression of the eruptions.

How useful is periodic acid-Schiff stain to detect fungi in biopsies from dermatoses of the palms and soles?

BACKGROUND: Periodic acid-Shiff (PAS) stain may help to diagnose fungal infection in biopsies from dermatoses of the palms and soles. It is questionable whether PAS stain should be used routinely or only when tinea is suspected clinically. METHODS: A total of 195 consecutive punch biopsies of dermatoses from the palms (90) or soles (105) were stained with PAS, regardless of the clinical differential diagnosis. RESULTS: PAS stain showed fungi in the corneal layer of 6 (3%) of the 195 biopsies. Tinea was included in the differential diagnosis in 48 cases, of which 3 (6%) were PAS positive. PAS stain was also positive in 3 (2%) of 147 cases in which tinea was not suspected clinically. All 6 PAS-positive cases were detected in reaction patterns not readily classified as particular diagnostic entities: non-inflammatory keratoderma (2, 11%), chronic lichenified dermatitis (2, 6%), spongiotic psoriasiform dermatitis (1, 2%), and spongiotic dermatitis (1, 4%). CONCLUSIONS: There is a low concordance rate between the clinical suspicion and the actual demonstration of fungi by PAS stain in dermatoses of the palms and soles. Routine PAS stains in non-suspected cases have a relatively low yield, which may be improved by limiting the PAS stain to reaction patterns not readily classified as particular diagnostic entities.

Assessment of the Prevalence of Mucosal Involvement in Bullous Pemphigoid.

Importance: The prevalence of mucosal involvement in bullous pemphigoid (BP) is inconsistent. Nonoral mucosal involvement was reported anecdotally in few patients with BP. Objective: To evaluate the prevalence of mucosal involvement in patients with BP, and to characterize the subgroup of patients with mucosal lesions. Design, Setting, and Participants: A retrospective cohort study was performed including 328 consecutive patients diagnosed with immunopathologically validated BP at a tertiary care referral center for autoimmune bullous diseases in northern Israel between January 1, 2000, and December 31, 2017. Main Outcome and Measures: The study was conducted to estimate the prevalence and distribution of mucosal involvement among patients with BP. Patients with mucosal involvement were compared with the remaining BP patients regarding clinical and immunological features, laboratory analyses, and treatments. Results: The study cohort included 139 (42.4%) male and 189 (57.6%) female patients, with a mean (SD) age of 78.0 (11.8) years at presentation. Fifty-six patients (17.1%) presented with mucosal lesions. The oral mucosa was the most frequently affected mucosal surface (n = 44; 13.7%), followed by the laryngeal (n = 16; 4.9%) and the genital (n = 10; 3.0%) mucosae. Among patients with oral lesions, the most involved oral structures were the buccal mucosa (n = 25; 55.6%) and the soft palate (n = 24; 53.3%). Compared with other patients with BP, patients with mucosal involvement were younger (71.8 [14.4] years vs 79.3 [10.8] years; P < .001), presented more frequently with extensive disease (55.4% vs 39.7%; P = .002), had less peripheral eosinophilia (17.8% vs 41.9%; P < .001), and were treated with higher doses of corticosteroids (prednisone >1 mg/kg: 67.9% vs 51.8%; P = .03). Conclusions and Relevance: Mucosal lesions are present in a notable subgroup of patients with BP and are associated with disease severity. Laryngeal involvement is more common than previously appreciated.

Mycophenolate mofetil therapy in adult patients with recalcitrant atopic dermatitis.

BACKGROUND: Patients with severe atopic dermatitis (AD) may require potent immunosuppressive therapy to control their disease. Mycophenolate mofetil (MMF) has been suggested as a safe and effective drug in these cases. OBJECTIVES: To investigate effectiveness and tolerability of oral MMF in adult patients with severe recalcitrant AD. METHODS: During the years 2010-2017 oral MMF 2-3 g/day was administered to adult patients with severe recalcitrant AD who failed other major systemic drugs, or where other drugs, including cyclosporine (CSA), methotrexate, and azathioprine, were contraindicated. RESULTS: Of 9 consecutive adult patients, 4 (44%) responded completely, 2 (22%) had partial response, and 3 (33%) did not respond at all. The MMF therapy was continued for 5-36 months (average 21 months) without major side effects. CONCLUSIONS: Oral MMF may be an effective drug in AD. Due to its good safety profile, it may be recommended as a first-line systemic therapy, or successive to CSA in the long term.

Pigmented Facial Contact Dermatitis to Benzyl Salicylate: A Comparative Histopathological and Immunohistochemical Study of the Involved Skin and the Positive Patch Test Site.

Pigmented contact dermatitis (PCD) is a noneczematous variant of allergic contact dermatitis, and benzyl salicylate is one of its causes. This type of PCD shows nonlichenoid interface dermatitis with pigment incontinence. We aimed to characterize the earliest histopathological changes of this reaction. A 51-year-old man presented with persistent facial eruption composed of hyperpigmented and hypopigmented macules due to exposure to benzyl salicylate present in his aftershave. The biopsies obtained from hyperpigmented and hypopigmented macules, and from the positive patch test site to benzyl salicylate, showed a nonlichenoid focal vacuolar interface dermatitis with mononuclear cells in the papillary dermis and around the pilosebaceous units, along with melanophages. A MART-1 immunostain showed intact melanocytes in all 3 biopsies. A Fontana-Masson stain demonstrated intact melanin in the basal cell layer of a facial hyperpigmented macule and the patch test site, but melanin was reduced in the biopsy taken from a hypopigmented facial macule. There were more epidermal and dermal CD1a+ Langerhans cells in the patch test biopsy than in the other 2 biopsies. Most of the mononuclear cells were CD3+. The CD4+ to CD8+ ratio was approximately 1:1 in the facial macules; yet, CD4+ cells outnumbered CD8+ cells in the patch test biopsy. There were a few TIA-1+ cells in all 3 biopsies. In conclusion, the earliest histopathological and immunophenotypical events in PCD due to benzyl salicylate are similar to those of longer-standing lesions, i.e., a nonlichenoid focal interface dermatitis involving the epidermis and pilosebaceous unit, along with dermal melanophages.

Hydroxychloroquine sulphate therapy of erosive oral lichen planus.

BACKGROUND/OBJECTIVES: Erosive oral lichen planus (LP) may be painful and debilitating. Symptomatic oral LP has been treated with a wide spectrum of topical and systemic therapies, but few have been evaluated in large series. Hydroxychloroquine is suggested to be effective in oral LP. METHODS: Twenty-one consecutive patients with erosive, biopsy-confirmed oral LP were prescribed. hydroxychloroquine sulphate 400 mg/day. Symptomatic improvement was evaluated by means of a visual analogue scale into three groups: no change, moderate to marked improvement and complete remission. RESULTS: Five (24%) patients obtained complete remission, 12 (57%) patients showed moderate to marked improvement, 3 (14%) patients did not improve at all and in one patient therapy was terminated after 1 month due to side effects. Response to therapy was observed after 2-4 months. Side effects which ultimately led to termination of therapy in three patients were elevated creatinine serum levels (after 1 month), visual field defects (after 8 months) and hyperpigmentation (after 24 months). Among six patients who responded to therapy, three flared on stopping. CONCLUSIONS: Hydroxychloroquine sulphate may be effective and relatively safe treatment for erosive oral LP.

Mortality in Patients with Bullous Pemphigoid: A Retrospective Cohort Study, Systematic Review and Meta-analysis.

There is little consensus regarding mortality data in bullous pemphigoid (BP). The aim of this study was to evaluate mortality among a relatively large cohort of Israeli patients with BP and to perform a meta-analysis synthesizing existing data on 1-year mortality rates of patients with BP. This retrospective cohort study of 287 patients diagnosed with BP between 2000 and 2015 compared the mortality of patients with BP with age- and sex-matched control subjects in the general population. The results showed 1-, 5- and 10-year mortality rates of 26.9%, 56.9% and 69.5%, respectively, and a 3.4-fold higher risk of death. A systematic review and meta-analysis were then performed using a random effects model. Including the current study, 25 studies comprising 4,594 patients met the eligibility criteria. The pooled estimate of 1-year mortality rate was 23.5% (95% confidence interval 20.2-26.8; I2=81%; p < 0.001). The pooled 1-year mortality rate of European cohorts was prominently higher relative to the pooled rates of cohorts from the USA and Asia.